Our current focus is to use candidate gene studies to identify molecules that affect the outcome in chronic nerve pain conditions. Identification of such genes would encourage pharmacologists to develop new drug treatments to imitate pain-reducing gene effects. Our primary clinical condition of interest is lumbar root pain from herniated intervertebral disc. This is one of the most costly chronic pain conditions in the US population. It is ideal for candidate gene studies because the anatomy and clinical presentation of disc herniation is so uniform, and it is common enough to allow the collection of the large numbers of patients essential to candidate gene studies. Because the physiology of the nerve root is similar in the lumbar spine and in the facial region (trigeminal nerve root) we will use results from the common spinal condition to understand less common orofacial nerve root pain conditions, including idiopathic trigeminal neuralgia (tic douloureaux) and traumatic and cancer related trigeminal nerve disorders. We are also carrying out randomized controlled trials of treatments for chronic lumbar nerve root pain, and providing our genetics expertise to other research groups who study other kinds of pain disorders and mood disorders.[unreadable] [unreadable] Our most important result was to show that a common variant that reduces function of the GCH1 gene appears to protect against pain in patients undergoing lumbar spine surgery for sciatica, and in normal humans given experimental pain stimuli (Tegeder et al., Nature Medicine, 2006.) In these studies, we collaborated with the Woolf lab at Harvard, which identified a critical role of this gene in rats with three types of nerve injuries, and with investigators at the University of Florida and North Carolina dental schools. The Harvard group is beginning to explore the feasibility of developing drugs to reduce the function of this gene, to mimic the pain resistance found in people with this variant. We also examined the variability of the reduction in movement reported among patients with subacute disc herniation with sciatica. We found that a common haplotype in the GABA-A beta-1 receptor was associated with less reduction in movement than other haplotypes, suggesting that this might function as an endogenous muscle relaxant. If this finding confirmed, this may point to a new class of drugs for treatment of acute pain that may reduce the disability caused by pain.[unreadable] [unreadable] Our groups other genetics publications this year included the description of the effects of variants in the gene for the galanin-3-receptor (Belfer et al., Genes, Brain, and Behavior) on the risk of alcoholism in Finns and Native American tribes, and the lack of effect of chronic pain on gonadal and adrenal function at hypothalamic, pituitary, and end-organ levels (Khoromi et al., J Clin Endocrin Metab, 2006). If pain patients develop hormonal abnormalities, other causes must therefore be sought.[unreadable] [unreadable] Our group also completed several clinical trials in patients with chronic pain. Morphine, nortriptyline and their combination did not reduce pain more than placebo in patients with chronic sciatica, suggesting that this common type of nerve pain is more resistant to treatmen. A clinical trial of magnetic belt treatment of chronic nerve root pain also showed an average pain reduction of 18% compared to a control treatment, but this was not statistically significant (Khoromi et al., J Pain Symptom Management, 2007).